Summary: Age-related macular degeneration (AMD) represents the most common cause of blindness in patients over the age of 60. While both hereditary and environmental factors appear to play a role in the pathogenesis of the disease, the interaction between these factors is unclear. Based on laboratory evidence, one proposed hypothesis for this disease focuses on an altered injury response program of the retinal pigment epithelium. Studies were completed which examined retinal pigment epithelial cells from autopsy specimens from aged eyes. Biopsies were being taken of these eyes and electron microscopic confirmation of the presence or absence of age-related macular degeneration changes is being performed. As above, sublethal injury is initiated and both a microarray analysis as well as a proteomic analysis of the differences between age-matched control and affected cells is being initiated. This is the first study of its kind to study so extensive the genetic responses of RPE cells taken when the diagnosis of AMD has been confirmed by the gold standard of accuracy, electron microscopy. In addition, SNP analysis of these cells for mutations within in the complement factor H (CFH) gene has been performed. To date, several interesting observations have been made. First, there appears to be a high discordance between a histologic diagnosis of AMD and the presence and absence of relevant mutations in the CFH gene. When expression profiles are segregated and analyzed based on histologic identification, some differences appear but appear to be smaller than would have been predicated. There is segregation of the microarray data with dependence on both CFH mutation status and the expression of several co-factor genes. A further expansion of these studies is the identification and analysis of peripheral potential vascular progenitor cells in patients with AMD. The hypothesis that serves as the generator for this work is that circulating endothelial progenitor cells may be recruited to the site of choroidal neovascularization. To date, two main types of cells have been identified from the peripheral circulation with both control and AMD patients which appear to express endothelial markers once placed in culture. One cell type, termed late outgrowth endothelial cells (OEC's) appear after 2 - 3 weeks in culture, require more specific culture conditions, have a high proliferative capacity and have a variable appearance and growth profile based on the age and disease state of the patient. The other cell type, termed endothelial progenitor cell (EPC'S), appears earlier in the culture and originates from floating or nonadherent cell population. However, as opposed to OEC's, these cells do not demonstrate a high proliferate capacity but are variable in terms of cytokine and growth factor expression. Both functional and microarray data has demonstrated that certain characterisitics of these cells including their ability to proliferate in culture and the number of initial clusters which are plated appear to be positively correlated with the neovascular form of AMD. On-going work is now determining certain marker genes which will allow for more rapid screening of a larger population of AMD patients at high risk to develop CNV,